Protein kinase c mediates lps- and phorbol-induced cardiac cell
nitric oxide synthase activity and hypocontractility.
McKenna, Thomas M., Shaohua Li, and Shiying Tao.
Septic Shock Research Program, Naval Medical Research Institute,
Bethesda, MD 20889
APStracts 2:0263H, 1995.
Lipopolysaccharide (LPS) treatment impairs cardiac myocyte
contractility in a nitric oxide synthase (NOS)-dependent manner. The
objective of this study was to assess whether protein kinase C (PKC)
transduces the LPS signal into an enhanced NOS activity in rat
cardiac myocytes. LPS (100 ng/ml) stimulated myocyte PKC activity,
inducible NOS (iNOS) expression, and NOS activity in a time- and
protein synthesis-dependent fashion. Directly activating PKC with
-phorbol 12,13-dibutyrate ( -PDB) also induced myocyte iNOS synthesis
and NOS activity and reduced electrically-stimulated contractility,
while the inactive [alpha]-PDB was ineffectual. Contractility could
be restored to -PDB incubated cells by superfusion with the NOS
inhibitor N -nitro-L-arginine methyl ester. PKC blockade with
sphingosine, chelerythrine, or calphostin-C precluded LPS and -PDB
induced increases in NOS activity and protected contractility.
Depletion of PKC by 18 h incubation with -PDB in the presence of
chelerythrine also blocked acquisition of enhanced NOS activity and
contractile dysfunction when the myocytes were subsequently exposed
to LPS. These findings suggest that PKC is a significant
intracellular mediator for the effects of LPS on cardiac cell nitric
oxide synthase activity and contractile function.
Received 6 December 1994; accepted in final form 7 June 1995.
APS Manuscript Number H1069-4.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 6 July 1995.